Gamma-aminobutyric acid (GABA) has been identified as a major inhibitory neurotransmitter, and agents that modulate GABAergic neurotransmission are used extensively in the treatment of conditions such as epilepsy, anxiety and depression. Two families of GABA receptor have been described, termed GABAA and GABAB.
The GABAA receptor is a member of the ligand-gated ion channel superfamily. The functional receptor generally comprises a number of subunits. At least 16 such subunits have been characterized, including 6 alpha subunits (α1-6), 3 beta subunits (β1-3), 3 gamma subunits (γ1-3), and delta, epsilon, pi and theta subunits (δ, ε, π, θ). Most GABAA receptors are made up of 2 alpha, 2 beta and one gamma subunit. Several drug binding sites have been described. These include the binding site for the endogenous ligand (GABA), and allosteric binding sites. Drugs that bind at the allosteric binding sites may be positive allosteric modulators, which increase responsiveness, negative allosteric modulators, which decrease receptor responsiveness, or neutral, which term refers to compounds that bind to the allosteric binding sites without modulating the activity of the receptor. Recent evidence has suggested that GABAA receptors comprising either the α2 or α3 subunit (herein termed GABAA α2/3 receptors) may be involved in certain pain states, and that positive allosteric modulators of these receptors may be useful analgesics (Mirza, N. R. and Munro, G., Drug News and Perspectives, 2010, 23(6), 351-360).
4-(Biphenyl-3-yl)-1H-pyrazolo[3,4-c]pyridazine derivatives have not been reported as having an interaction with GABAA α2/3 receptors. International patent application PCT/IB2013/60631 (published as WO2014/091368) discloses 4-(biphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine derivatives that have affinity for the α2, α3 and/or α5 subunits.
There is a continuing interest in finding new compounds that interact with GABAA receptors, and particularly for compounds that have a reduced propensity for causing the adverse events such as drowsiness that are associated with the currently available GABAA modulators such as benzodiazepines. It is thought that these adverse effects are a result of modulation of α1 subunit-containing receptors, and so preferred compounds will have a high affinity for the α2/3 subunit-containing receptors with good efficacy as positive allosteric modulators, while having low efficacy at receptors with other a subunits, particularly the α1 subunit-containing receptors.
These drug candidates should additionally have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.